Chronic wasting disease of deer and elk in transgenic mice: oral transmission and pathobiology.
Chronic wasting disease of deer and elk in transgenic mice: oral transmission and pathobiology.
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转基因小鼠中鹿和麋鹿的慢性消耗性疾病：口腔传播和病理学。
DOI：
10.1016/j.virol.2007.03.032
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发表时间：
2007
期刊：
影响因子：
3.7
通讯作者：
Oldstone,MichaelBA
中科院分区：
文献类型：
--
作者：
Trifilo,MatthewJ;Ying,Ge;Teng,Chao;Oldstone,MichaelBA
为了研究鹿和麋鹿慢性消耗性疾病(CWD)的发病机制，在小鼠PrP启动子的转录调控下，获得了表达鹿PrP的转基因小鼠，PrP含有一个氨基酸(AA)96位的甘氨酸和一个AA 225位的丝氨酸。该基因被引入PrP基因缺陷小鼠体内。正如预期的那样，非TG小鼠和PrP Ko小鼠在脑内接种时都不容易感染(I.C.)或口服CWD脑材料(取自6头骡鹿的瘙痒池)，并随访600多天(Dpi)。鹿PrP TG小鼠对I.C.不敏感。接种小鼠瘙痒病。相反，发生了一种致命的神经系统疾病，并伴有鹿PrPsen转变为PrPres，通过免疫印迹和免疫组织化学方法。将CWD脑接种到两个TG小鼠品系中(杂合的TG品系33为312+32 Dpi[平均+2标准差]，杂合的TG品系39为275±46 Dpi，纯合子的TG品系33为210 Dpi)，或口服接种后(纯合子的TG品系33为381±55 Dpi，纯合子的TG品系39为370±26 Dpi)。经口接种CWD脑后，在临床健康的小鼠舌背后200天观察到PrPreS，主要分布在浆液腺和粘液腺、肠道、脾边缘区解剖上类似滤泡状树突状细胞和巨噬细胞的大细胞以及嗅球和脑干中，而在感染小鼠的小脑、大脑皮质或海马体、心、肺和肝脏中未见PrPreS。在小鼠临床患病350天后，小脑、大脑皮层和海马体PrPres呈阳性，并显示大量海绵体、神经元脱落、胶质增生和花斑块。
To study the pathogenesis of chronic wasting disease (CWD) in deer and elk, transgenic (tg) mice were generated that expressed the prion protein (PrP) of deer containing a glycine at amino acid (aa) 96 and a serine at aa 225 under transcriptional control of the murine PrP promoter. This construct was introduced into murine PrP-deficient mice. As anticipated, neither non-tg mice nor PrP ko mice were susceptible when inoculated intracerebrally (i.c.) or orally with CWD brain material (scrapie pool from six mule deer) and followed for 600+ days (dpi). Deer PrP tg mice were not susceptible to i.c. inoculation with murine scrapie. In contrast, a fatal neurologic disease occurred accompanied by conversion of deer PrPsen to PrPres by western blot and immunohistochemistry after either i.c. inoculation with CWD brain into two lines of tg mice studied (312+32 dpi [mean+2 standard errors] for the heterozygous tg line 33, 275+46 dpi for the heterozygous tg line 39 and 210 dpi for the homozygous tg line 33) or after oral inoculation (381+55 dpi for the homozygous tg line 33 and 370+26 dpi for the homozygous tg line 39). Kinetically, following oral inoculation of CWD brain, PrPres was observed by day 200 when mice were clinically healthy in the posterior surface of the dorsum of the tongue primarily in serous and mucous glands, in the intestines, in large cells at the splenic marginal zone that anatomically resembled follicular dendritic cells and macrophages and in the olfactory bulb and brain stem but did not occur in the cerebellum, cerebral cortex or hippocampus or in hearts, lungs and livers of infected mice. After 350 days when mice become clinically ill the cerebellum, cerebral cortex and hippocampus became positive for PrPres and displayed massive spongiosis, neuronal drop out, gliosis and florid plaques.